TREATMENT OF EAE USING GENETICALLY MODIFIED CTL

自身反应性T淋巴细胞（ATL）是关键的调节和免疫调节细胞。 多发性硬化症和其他自身免疫性疾病的效应细胞 疾病 这些ATL的根除可以改善或治愈这种疾病。 疾病 能够选择性靶向ATL的疗法不是 临床可用。 该提案描述了一个 一种使用基因修饰的细胞溶解T细胞的新疗法， 淋巴细胞（GM-CTL）以选择性地消除ATL。 GM- CTL将用嵌合受体转染，所述嵌合受体能够 识别ATL并激活GM-CTL。 这种受体将 主要组织相容性复合体（MHC） α和β链，B.共价连接的抗原肽，和 C. T细胞受体ζ链的激活域。 的 ALT T细胞受体将特异性地与NHC相互作用- 嵌合受体的肽复合物。 这种互动将 激活GM-cTL，进而杀死ATL。 通过使用 GM-CTL选择性消除ATL，应该可以 调节或消除正在进行的自身免疫性疾病。 这将是 使用良好表征的小鼠模型测试了多个 硬化症和接种后脑脊髓炎，实验性 过敏性脑脊髓炎（EAE）。嵌合构建体设计将 使用GM-CTL活性的体外测定进行优化。 GM-CTL 然后将其过继转移到小鼠体内， 在EAE的诱导下或诱导后。 病理临床 将对结果进行评估。 这些实验将 因此，提供初步研究评估的有用性转基因- CTL治疗自身免疫性神经系统疾病 它将建立 类似地使用GM-CTL作为治疗的先例， 人类自身免疫性疾病

Autoreactive T lymphocytes (ATL) are critical regulatory and effector cells for multiple sclerosis and other autoimmune diseases. Eradication of these ATL may ameliorate or cure such diseases. Therapies capable of selectively targeting ATL are not available clinically. This proposal describes the development of a novel therapy that uses genetically modified cytolytic T lymphocytes (GM-CTL) to selectively eliminate ATL. The GM- CTL will be transfected with a chimeric receptor capable of both recognizing ATL and activating the GM-CTL. This receptor will consist of: a class II major histocompatibility complex (MHC) alpha and beta chains, b. covalently linked antigenic peptide, and c. the activation domain of the T cell receptor zeta chain. The ALT T-cell receptor will specifically interact with the NHC- peptide complex of the chimeric receptor. This interaction will activate the GM-cTL, which in turn will kill the ATL. By using GM-CTL to selectively eliminate ATL it should be possible to modulate or abrogate ongoing autoimmune disease. This will be tested using a well characterized murine model for multiple sclerosis and post-vaccination encephalomyelitis, experimental allergic encephalomyelitis (EAE). Chimeric construct design will be optimized using in vitro assays of GM-CTL activity. GM-CTL will then be adoptively transferred into mice prior to, concurrent with, or following the induction of EAE. Pathologic and clinical measures of outcome will be assessed. These experiments will thus provide the initial studies assessing the usefulness of GM- CTL in treating autoimmune neurologic disease. It will establish a precedent for the analogous use of GM-CTL as a therapy for human autoimmune disease.